Peptide proteinaceous drug nasal powder composition

ABSTRACT

A peptide proteinaceous drug nasal powder composition containing (i) an absorption accelerant comprised of a compound, or its salt, having in its molecule a group expressed by the formula (I): ##STR1## wherein, ##STR2## indicates a cyclohexane ring or a benzene ring which may be substituted at least one of its 3-position, 4-position, and 5-position and n is an integer of 1 to 3 and (ii) a therapeutically effective amount of a peptide proteinaceous drug.

TECHNICAL FIELD

The present invention relates to a peptide proteinaceous drug nasalpowder composition having an improved absorbency. More specifically, itrelates to a peptide proteinaceous drug nasal powder composition, whichis improved in absorption from the mucous membrane of the nasal cavityto the blood stream of the entire body by suppression of thedecomposition of the peptide proteinaceous drug administered to thenasal cavity by an absorption accelerant having specified groups.

BACKGROUND ART

Along with the progress in biotechnology in recent years, there havebeen a succession of discoveries of peptide roteinaceous compoundshaving physiological activity. Production of these compounds has becomeeasy as well. Many of these peptide proteinaceous drugs are used only asinjections due to the low level of their stability and absorbency.However, these drugs are preferably administered in multiple dosages fortherapeutic reasons. Administration by injection in this case places aburden on the patient due to the pain to the patient and the need forvisiting a hospital.

Therefore, other various methods of administration have been examined asnon-invasive methods of administration of peptide proteinaceous drugs totake the place of injections, for example, the method of rectaladministration by suppositories (J. Pharma., 33 334 (1981)), bronchialadministration (Diabetes 20 552 (1971)), instillation administration(Abstracts of Diabetes Society 237 (1964)), etc. All of these methods,however, are hard to commercialize due to the difficulties that higherdosages are required than with injections and the absorption tends tofluctuate.

On the other hand, the nasal cavity has a well developed system of bloodvessels in the mesothelium layer and is able to absorb a drug quicklyand with little variation. Due to these advantages, the nasaladministration method has come into attention. At the present time,however, sufficient absorption cannot be obtained, and therefore,various studies are under way to raise the absorbency.

For example, Nolte et al. (Hormone Metabolic Research 22, 170-174,1990), Moses (Pharmaceutisch Week-blad-Scientific Edition 10, 45-46,1988), Bruce et al. (Diabetic Medicine 8, 366-370,1991), etc. report onnasal administration of insulin containing sodium glycocholate or sodiumtaurofusidate as absorption accelerants. These preparations containingabsorption accelerants, however, have problems with irritation to thenasal mucous membrane, and therefore, have not been commercialized.

As the major causes for the low absorbency of a peptide proteinaceousdrug from the nasal mucous membrane, Illum (Trends Biotechnol 9,284-289, 1991), W. A. Lee (Biopharm. Manuf. 1, 30-37, 1988), Edman(Advanced Drug Delivery Reviews 8, 165-177, 1992), etc. have mentionedthe low level of drug permeability into the mucous membrane, theelimination of the drug by ciliary movement, and the degradation of thedrug by the protease in the nasal cavity.

Among these, as a major discovery relating to the protease in the nasalcavity, O'Hagan et al. (Pharm. Res. 7, 772 (1990)), Hussain et al.(Pharm. Res. 6, 186 (1989)), showed by animal experiments using rats andsheep that the nasal absorption of insulin, growth hormone, enkephalin,and other peptide proteinaceous drugs is improved by administrationtogether with amastatin, bestatin, α-aminoboronic acid, or otheraminopeptidase inhibitors.

Further, Illum et al. (Japanese National Disclosure (Kohyo) No.2-503915) mentioned that effective protease inhibitors for nasalpreparations in studies of rats, rabbits, and sheep were actinonin,amastatin, bestatin, chloroacetyl-HO-Leu-Ala-Gly-NH₂, diprotin A and B,evelactone A and B, E- 64, H-(tBu)-Phe-Pro-OH, kallikrein inhibitor I,chymotrypsin inhibitor I, trypsin inhibitor III- 0, leupeptin,pepstatin, phosphoramidone, aprotinin, chymostatin, and benzamidine.

Further, Morimoto et al. (111 and 112 Ann. Meetings of JPN Pharm, Soc.)showed by by animal experiments using rats that the nasal absorbency ofsalmon calcitonin was improved by administering it with aprotinin, TAME(tosyl arginine methyl ester), which was a synthetic substrate oftrypsin, or other trypsin inhibitors.

Further, the present inventors confirmed by animal experiments usingrabbits that in the nasal cavity of rabbits, salmon calcitonin, LHRH,insulin, and other peptide proteinaceous drugs were cleaved at the Cterminal of the Leu in their primary structures and that the nasalabsorbency of these is improved by administering them with achymotrypsin inhibitor (for example, see Japanese Patent Application No.5-130993 i.e., Japanese Unexamined Patent Publication No. 6-321804.

These findings, however, were all based on animal experiments usingrats, sheep, and rabbits and the significance for humans is unclear.Accordingly, at the present time, it is not clear if the methods forimproving the nasal absorbency of peptide proteinaceous drugs in rats,sheep, rabbits, and other animals would be effective for humans.

DISCLOSURE OF INVENTION

Accordingly, the present invention provides a peptide proteinaceous drugnasal powder composition which, by combined use of a protease inhibitor,suppresses the degradation of the peptide proteinaceous drug in thehuman nasal cavity by the action of the enzyme, is improved in the nasalabsorbency, and is safe to the body.

In accordance with the present invention, there is provided a peptideproteinaceous drug nasal powder composition comprising (i) an absorptionaccelerant comprising a compound, or its salt, having in its molecule agroup expressed by the formula (I): ##STR3## (wherein, ##STR4##indicates a cyclohexane ring or a benzene ring which may be substitutedat least one of its 3-position, 4-position, and 5-position and n is aninteger of 1 to 3) and (ii) a therapeutically effective amount of apeptide proteinaceous drug.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will now be explained in further detail withreference to the drawings; wherein:

FIG. 1 is a graph showing the changes along with time of theconcentration of salmon calcitonin in the plasma in normal humanvolunteers after administration of a calcitonin nasal powdercomposition;

FIG. 2 is a graph showing the changes along with time of theconcentration of GH in the plasma in normal human volunteers afteradministration of a GHRH nasal powder composition;

FIG. 3 is a graph showing the changes along with time of theconcentration of LH in the plasma in normal human volunteers afteradministration of an LHRH nasal powder composition;

FIG. 4 is a graph showing the changes along with time of theconcentration of salmon calcitonin in the plasma in normal humanvolunteers in Example 4 after administration of a calcitonin nasalpowder composition; and

FIG. 5 shows the concentration of calcitonin in the plasma in the caseof administration of nasal preparations of the present invention inExamples 5 and 6 and nasal preparations in Control Examples 1 and 2.

BEST MODE FOR CARRYING OUT THE INVENTION

As mentioned above, the present inventors found that a compound havingthe specific formula (I) suppressed the degradation of peptideproteinaceous drugs in the human nasal cavity and improves the nasalabsorbency.

It should be noted that, as is clear from the later ReferenceExperiments and Examples, the compound having the above-mentionedformula (I), that is, the absorption accelerant for providing a peptideproteinaceous drug preparation which suppresses the degradation ofpeptide proteinaceous drug in the human nasal cavity by the action ofthe protease and improves the nasal absorbency, as aimed at by thepresent invention, may be said to be a compound where the aminomethylgroup, aminoethyl group, and aminopropyl group have attached to them acyclohexane ring or benzene ring that cannot cover these groupsspatially due to the intermolecular electrostatic interaction orrigidity etc. Accordingly, also included in the absorption accelerant ofthe present invention are compounds in which the substituents andcyclohexane and benzene are substituted by other substituents, forexample, chain (straight chain, branched) or cyclic saturated orunsaturated hydrocarbon groups etc. to the extent to which it isnaturally assumed that these groups will not be covered spatially due tothe intermolecular electrostatic interaction or rigidity etc.

That is, the compound of formula (I) has a NH₂ -(CH₂)_(n) -group. It isessential that this is bonded together with a cyclohexane ring orbenzene ring. With just this structure, the cyclohexane ring or benzenering may have a substituent at the 3-, 4-, and/or 5-positionthree-dimensionally separated from the NH₂ -(CH₂)_(n) -group. Thesubstituent is not particularly limited so long as it is a group whichis stable as a preparation in the case of being made a powder and whichposes no safety problem in terms of irritation etc. when administered toa human patient. More specifically, the compound having the group of thestructure of formula (I) may be expressed by the following generalformula (II): ##STR5## wherein, n is an integer of 1 to 3, preferably 1to 2, and R¹, R² and R³ are, independently, a group selected from ahydrogen atom, phosphoric acid group, cyano group, COOR, COR, OR',S(O)_(p) R', NR'R", carbamoyl group, SO₂ NH₂, and substitutable C₁ -C₂₀hydrocarbon group, wherein R represents a hydrogen atom; C₁ -C₆ loweralkyl group which may be substituted; or ##STR6## CH₂ CH₂ COOR', R' andR" epresent, independently, a hydrogen atom; C₁ -C₆ lower alkyl groupwhich may be substituted, phenyl group which may be substituted, or C₇-C₈ aralkyl group which may be substituted, and p is an integer of 0 to3.

In these R¹ to R³, as the C₁ -C₆ lower alkyl group, mention may be madeof a methyl group, ethyl group, n-propyl group, i-propyl group, n-butylgroup, i-butyl group, s-butyl group, t-butyl group, n-pentyl group,n-hexyl group, cyclopropyl group, and other straight chain or branchedchain or cyclic alkyl groups. Among these, a methyl group, ethyl group,n-butyl group, and other C₁ -C₄ lower alkyl groups may be mentioned asbeing preferable. Further, as the C₇ -C₈ aralkyl group, mention may bemade of a benzyl group and phenylethyl group.

Further, the C₁ -C₂₀ hydrocarbon group means a saturated or unsaturatedchain (straight chain or branched) or cyclic hydrocarbon group. Forexample, mention may be made of those similar to those illustrated asthe C₁ -C₆ lower alkyl group and those which, when unsaturated, have oneor more double bonds and/or triple bounds, such as a heptyl group, decylgroup, eicosyl group, 2,2-dimethyloctyl group, cyclohexylbutyl group,propenyl group, isopentenyl group, 8-heptadecenyl group, and8,11-heptadecadienyl group. As the C₁ -C₂₀ hydrocarbon group,preferably, mention may be made of a C₁ -C₁₅ hydrocarbon group, morepreferably a C₁ -C₁₀ hydrocarbon group.

As a specific example of the COOR of the R¹ to R³, mention may be madeof a carboxyl group, methoxycarbonyl group, ethoxycarbonyl group,hexyloxycarbonyl group, and ##STR7## and as a specific example of theCOR, mention may be made of formyl group, acetyl group, propionyl group,and ##STR8##

Further, as specific examples of the S(O)_(p) R', mention may be made ofa thiol group, sulfenic acid group, sulfinic acid group, sulfonic acidgroup, methylthiol group, isopropyl thiol group, isopropyl sulfinylgroup, isopropyl sulfonyl group, pentyl sulfonyl group, phenyl thiolgroup, phenyl sulfonyl group, etc. Further, as specific examples ofNR'R", mention may be made of an amine group, dimethyl amine group,diethyl amine group, benzyl amine group, phenethyl amine group, etc.

Further, as specific examples of the OR', mention may be made of ahydroxyl group, methoxyl group, ethoxyl group, (n-, i-) propoxyl group,(n-, i-, s-, t-) butoxyl group, hexyloxyl group, cyclopropylmethyloxylgroup, phenyloxyl group, phenethylloxyl group, etc.

The R¹ to R³ of the present invention may, when having a C₁ -C₂₀hydrocarbon group; C₁ -C₆ lower alkyl group, phenyl group, or C₇ -C₈aralkyl group, further have substituents at these groups. As suchsubstituents, mention may be made of the phosphoric acid group, cyanogroup, COOR, COR, OR', S(O)_(p) R', NR'R", carbamoyl group, and SO₂ NH₂exemplified as R¹ to R³.

As the absorption accelerant of the present invention, mention may bemade of the compounds in formula (I) or (II), wherein n=1 or 2 mentionedas preferable.

As the substituent on the cyclohexane ring or benzene ring in theabove-mentioned formula (I) or (II), mention may be made of asubstituent selected from COOR, COR, OR', SO₂ NH₂ and a C₁ -C₁₀hydrocarbon group among those illustrated as R¹ to R³.

In particular, in the above-mentioned formula (I) or (II), when thecyclic structure is a cyclohexane ring and n=1, preferable mention maybe made of a compound wherein the substituent is a group selected fromamong the group comprising a hydrogen atom, COOR, and COR. Inparticular, preferable mention may be made of a group selected from thegroup comprising a hydrogen atom, carboxyl group, ##STR9## In this case,specific mention may be made of the case where as the substituents as R¹to R³, R¹ to R³ are hydrogen atoms or R¹ and R³ are hydrogen atoms andR² is a group other than a hydrogen atom.

Further, when the cyclic structure is a benzene ring and n=1 or 2 in theabove-mentioned formula (I) or (II), preferable mention may be made of acompound wherein the substituent is a group selected from the groupcomprising a hydrogen atom, SO₂ NH₂, and OR', in particular, mention maybe made of the case where n=1 and the substituent is a group selectedfrom a hydrogen atom, carboxyl group, and SO₂ NH₂ (sulfamine) group orn=2 and the substituent is a hydrogen atom or hydroxyl group. In thiscase, specific mention may be made of the case where as the substituentsas R¹ to R³, when n=1, R¹ to R³ are hydrogen atoms or R¹ and R³ arehydrogen atoms and R² is a carboxyl group or SO₂ NH₂ group or, when n=2,R¹ is a hydrogen atom and R² and R³ are hydroxyl groups.

As further preferable examples of the compounds having the formula (I),mention may be made for example of cyclohexane methylamine, benzylamine,p- aminomethyl benzoic acid, tranexamic acid, rotraxate hydrochloride,cetraxate hydrochloride, mafenide acetate, dopamine hydrochloride, andtheir derivatives and acid addition salts and other salts.

Tranexamic acid has been known as a hemostyptic and is used at the timeof abnormal bleeding caused by systemic hyperfibrinolysis. Its safety inthe body has already been confirmed.

Rotraxate hydrochloride is known as a drug which has, as pharmaceuticalactions, (1) an action of increasing the blood flow in the gastricmucous membrane and (2) an action of promoting the secretion ofbicarbonate ion in the gastric mucous membrane and exhibits ananti-ulcer action that reinforces the function of protection of thegastric mucous membrane (see Japanese Examined Patent Publication(Kokoku) No. 60-36418).

Cetraxate hydrochloride is a drug which is used clinically foradaptation symptoms such as (1) lesions in the gastric mucous membrane(sores, bleeding, reddening, edema) due to the following ailments: acutegastritis and the acute exacerbated phase of chronic gastritis and (2)stomach ulcers (Nihon Iyakuhinshu 1993, p. 581, Yakuji Jihosha).

Mafenide acetate has been known in the past as an antibacterial agentand is effective for infection of wound surfaces by bacteria at the timeof burns (Nihon Yakuhin Yoran, 5th edition, p. 1140, Yakuji Jihosha).

Dopamine hydrochloride is a drug which is used clinically for adaptationsymptoms such as (1) acute circulatory insufficiency (cardiogenic shock,hemorraghic shock) and (2) acute circulatory insufficiency conditions(Nihon Iyakuhinshu 1993, p. 772, Yakuji Jihosha).

However, no method of use for improving the absorption by nasal powdersof peptide proteinaceous drugs has been known for tranexamic acid,rotraxate hydrochloride, cetraxate hydrochloride, mafenide acetate,dopamine hydrochloride, and other compounds of the present invention.Further, they are not included in the protease inhibitors mentioned inthe patent relating to nasal preparations of Illum et al.

Tranexamic acid suppresses the enzymatic degradation of the peptideproteinaceous drug in the human nasal cavity, so it could be guessedthat there is plasmin present in the human nasal cavity and that theplasmin cleaves down the peptide proteinaceous drug, but in the presentinvention the plasmin activity is low and, also, no effect of promotingnasal absorption was observed in by the ε-amino caproic acid, which is akind of plasmin inhibitor, so the possibility of plasmin playing a majorpart in the degradation of the peptide proteinaceous drug is denied.

Further, a trypsin-like enzyme is present in the human nasal cavity. Thepeptide proteinaceous drug administered in the nasal cavity is mainlycleaved by this enzyme. It is possible to improve the nasal absorbencyof peptide proteinaceous drugs by administering a trypsin inhibitor inthe human nasal cavity at the same time. However, tranexamic acid,rotraxate hydrochloride, cetraxate hydrochloride, mafenide acetate,dopamine hydrochloride, and other compounds of the present inventionhave no trypsin inhibiting activity, but maintain a higher effect thatthe effect of promotion of the rate of nasal absorption of a trypsininhibitor.

In other words, a trypsin-like enzyme exists in the human nasal cavityand the peptide proteinaceous drug administered in the nasal cavity ismainly broken down by that enzyme, but it is believed that the enzyme isrestrained more effectively than a trypsin inhibitor by the compound ofthe present invention, such as tranexamic acid, rotraxate hydrochloride,cetraxate hydrochloride, mafenide acetate, dopamine hydrochloride, etc.

Accordingly, tranexamic acid, rotraxate hydrochloride, cetraxatehydrochloride, mafenide acetate, dopamine hydrochloride, and othercompounds of the present invention can improve the stability of peptideproteinaceous drugs in the human nasal cavity and, accordingly, byadministering them together with peptide proteinaceous drugs in thenasal cavity, can improve the nasal absorbency of the peptideproteinaceous drugs.

The tranexamic acid used herein means trans-4-(aminomethyl) cyclohexanecarboxylic acid, but in the present invention use may also be made ofthe cis-form, namely, cis-4-(aminomethyl) cyclohexane carboxylic acid.

Further, the rotraxate hydrochloride means a hydrochloride of3-((p-(trans-4-aminomethylcyclohexylcarbonyl)phenyl)) propionic acid,but in the present invention, use may also be made of the cis-form,namely, a hydrochloride of3-(p-(cis-4-aminomethylcyclohexylcarbonyl)phenyl) propionic acid andalso other pharmaceutically allowable salts.

Further, the cetraxate hydrochloride means a hydrochloride oftrans-(4-aminomethyl) cyclohexane carboxylic acidp-(2-carboxyethyl)phenyl ester, but in the present invention, use mayalso be made of the cis-form, namely, cis-(4-aminomethyl) cyclohexanecarboxylic acid p-(2-carboxy ethyl)phenyl ester and also other differentpharmaceutically allowable salts.

Further, the mafenide acetate means an acetate of 4-(aminomethyl)benzenesulfamine, but in the present invention, use may also be made ofother pharmaceutically allowable salts.

Further, the dopamine hydrochloride means a hydrochloride of4-(2-aminoethyl)-1,2 benzenediol, but in the present invention, use mayalso be made of other pharmaceutically allowable salts.

The salt of the compound of the above formula (I) or (II) of the presentinvention means, for example, an acid addition salt, metal salt, orother pharmaceutically allowable salt. As a metal salt, mention may bemade of a sodium salt, potassium salt, and other alkali metal salt.

It should be noted that the acid of the acid addition salt is notlimited so long as it gives a pharmaceutically allowable acid additionsalt. For example, mention may be made of hydrochloric acid, sulfuricacid, phosphoric acid, and other inorganic acids and for example aceticacid, citric acid, tartaric acid, maleic acid, fumaric acid, and otherorganic acids, etc. In particular, preferable mention may be made ofhydrochloric acid, acetic acid, etc.

In the present invention, as the peptide proteinaceous drug, mention maybe made of at least one type of peptide proteinaceous drug selected fromthe group comprising calcitonins, somatostatin (GIF) and itsderivatives, parathyroid hormones (PTH), substance P, platelet derivedgrowth factors (PDGF), galanin, gastrin, neurokinins, interleukins,neurotensin, endo serine, growth hormone-releasing hormone (GHRH) andits derivatives, growth hormone releasing factor (GRF), luteinizinghormone-releasing hormone (LHRH) and its derivative, enkephalin and itsderivatives, secretin, bradykinin and its derivatives,adrenocorticotrophic hormone (ACTH) and its derivatives, insulins,glucagon, insulin growth factor (IGF), calcitonin gene related peptide(CGRP), vasopressin and its derivatives, atrial natrium peptide (ANP),erythropoietin, granulocyte colony stimuli factor (G-CSF), andmacrophage colony stimuli factor (M-CSF).

Among these, as preferable peptide proteinaceous drugs of the presentinvention, mention may be made of calcitonin, somatostatin (GIF), growthhormone releasing hormone (GHRH), luteinizing hormone-releasing hormone(LHRH), parathyroid hormone (PTH), or their derivatives.

Among these drugs, calcitonin is a peptide hormone which regulates themetabolism of calcium in the body. It works to obstruct the absorptionof calcium in the bones and to cause the reabsorption of calciumreleased from the kidneys. There are known salmon calcitonin, eelcalcitonin, human calcitonin, pig calcitonin, chicken calcitonin, bovinecalcitonin, sheep calcitonin, rat calcitonin, etc. In the presentinvention, use may be made of the derivatives of these calcitonins, forexample, elcatonin and other synthetic calcitonin and geneticallyengineered calcitonin.

Somatostatin (GIF) is a peptide comprised of 14 amino acid residueswhich act on the pituitary of vertebrates to suppress the release of GHand TSH and PRL and suppress secretion of gastrin, motilin, secretin,digestive enzymes, gastric acids, etc. in the gastropancreatic system.There are known human, rat, sheep, dove, angler, and pig types. Asderivatives of somatostatin, there are known for example ones likeoctoreotide acetate and other synthetic somatostatins wherein part ofthe amino acids are substituted with the D-form and several amino acidsare removed to give 6 to 7 amino acid residues. In the presentinvention, each of these may also be used.

The luteinizing hormone-releasing hormone (LHRH) is a peptide which actson the GTH cells of the anterior pituitary of vertebrates to cause therelease of LH and FSH. Human, pig, chicken, salmon, and eel types areknown. As the derivatives, there are known for example [D-Ser(t-Bu)⁶,des-Gly¹⁰ ethylamide] LHRH, [D-Ala-3(2-Naphtyl)⁶ ] LHRH, [D-Leu⁶,des-Gly¹⁰ ethylamide] LHRH, [D-Ser(t-Bu)⁶, aza-Gly¹⁰ ] LHRH,[N-Ac-D-Nal(2)¹, DpFPhe², D-Pal(3)³, Lys(Nic)⁵, D-Lys(Nic)⁶, Lys(iPr)⁸,D-Ala¹⁰ ] LHRH, and other synthetic LHRH and others with the 6-positionGly substituted with a D-form and others with the C-terminalglysine-amide substituted with alkylamine.

The growth hormone releasing hormone (GHRH) is a peptide which iscomprised of 43 to 44 amino acid residues which act on the anteriorpituitary of mammals and cause the release of growth hormones (GH).There are known human, rat, bovine, sheep, and pig types. As thederivatives, there are known ones with the C-terminal taken and made(1-29)-NH₂ etc. In the present invention, each of these may also beused.

Parathyroid hormone (PTH) is a peptide which is comprised of 84 aminoacid residues which act on bone and kidney and promote reabsorption ofCa²⁺. As its derivatives, there are known PTH₁₋₃₄ NH₂, which iscomprised of 1 to 34 amino acid residues of the N terminal etc. In thepresent invention, each of these may also be used.

As the combination of the absorption accelerant of the present inventionand the peptide proteinaceous drug, mention may be made of theabsorption accelerant having the above formula (I) or expressed by theformula (II) and a peptide proteinaceous drug. Among these, aspreferable combinations, mention may be made of (1) an absorptionaccelerant of tranexamic acid, rotraxate hydrochloride or cetraxatehydrochloride and, in this case, a peptide proteinaceous drug of, forexample, the above illustrated salmon calcitonin and other calcitonins,human somatostatin and other somatostatins, growth hormone accelerationhormones, and their derivatives, (2) an absorption accelerant ofmafenide or its pharmaceutically allowable acid addition salts, inparticular, mafenide acetate, and, in this case, a peptide proteinaceousdrug of, for example, the above illustrated salmon calcitonin and othercalcitonins, human somatostatin and other somatostatins, and theirderivatives, and (3) an absorption accelerant of dopamine or itspharmaceutically allowable acid addition salts, in particular, dopamichydrochloride, and, in this case, a peptide proteinaceous drug of, forexample, the above-illustrated salmon calcitonin and other calcitonins,human somatostatin and other somatostatins, and their derivatives.

The amount of the peptide proteinaceous drug in the present invention isthe therapeutically effective amount. The amount is specific to thedifferent types of peptide proteinaceous drug. The therapeuticallyeffective amount is usually preferably the same amount 1 to 20 times theamount of the peptide proteinaceous drug administered by injection, morepreferably 2 to 10 times the amount.

On the other hand, the amount of the absorption accelerant of thepresent invention is preferably approximately 0.1-10 parts by weightbased on 1 part by weight of the therapeutically effective amount of thepeptide proteinaceous drug, more preferably approximately 1 to 5 partsby weight, still more preferably 1 to 3 parts by weight. The amounts andratio in the case of mixing two or more types of absorption accelerantsare not particularly limited, but the total amount is preferably in thisrange.

The peptide proteinaceous drug nasal powder of the present invention isproduced by mixing one or more types of a fine powder peptideproteinaceous drug and the absorption accelerant of the presentinvention, for example, a water absorbing and water-insoluble base. Themixing is performed using a mortar, high speed mixer, or other usualmixer. The water-absorbing and water-insoluble base spoken of here meanssomething which has absorbency and insolubility on human nasal mucousmembrane or in an environment close to that, that is, with respect towater of a pH of about 7.4 and a temperature of about 36° C. to about37° C.

As preferable specific examples, mention may be made of water-absorbingand water-insoluble cellulose such as microcrystalline cellulose,α-cellulose, cross-linked sodium carboxymethylcellulose, and theirderivatives; water-absorbing and water-insoluble hydroxypropyl starch,carboxymethyl starch, cross-linked starch, amylose, amylopectin, pectinand their derivatives; water-absorbing and water-insoluble gum such asarabia gum, tragacanth gum, glucomannan and their derivatives; andcross-linked vinyl polymers such as polyvinylpolypyridone, cross-linkedpolyacrylic acid and its salt, cross-linked polyvinyl alcohol,polyhydroxyethylmethacrylate and their derivatives. Among these,water-absorbing and water-insoluble cellulose is preferable, inparticular, microcrystalline cellulose and its derivative are desirable.

It is also possible to add to this powder, in addition to the one ormore types of peptide proteinaceous drugs, the absorption accelerant ofthe present invention, and above-mentioned substrate, according torequirement, a known lubricant, preservative, antiseptic, deodorant,etc.

As a lubricant, for example, mention may be made of talc, stearic acidand its salts, etc.; as a colorant, for example, mention may be made ofcopper chlorophyll, β-carotene, red No. 2, blue No. 1, etc.; as apreservative, for example, mention may be made of stearic acid, ascorbicacid stearate, etc.; as an antiseptic, for example, mention may be madeof benzylkonium chloride and other quaternary ammonium compounds,paraoxybenzoic acid esters, phenols, chlorobutanol, etc.; and asdeodorant, mention may be made for example of menthol, citrusfragrances, etc.

The peptide proteinaceous drug nasal powder of the present invention isusually administered in the nasal cavity by the following method. Thatis, a capsule filled with the powder to set for example in an exclusivespray apparatus possessing a needle, the needle is made to penetrate itto make fine holes at the top and bottom of the capsule, then air is fedby a rubber ball etc. to make the powder spray out.

EXAMPLES

The present invention will now be explained in more detail in accordancewith the Reference Experiments and Examples, but of course the presentinvention is not limited to these Examples.

Reference Experiment 1

(1) A homogenate solution was prepared from human nasal mucosa to give 1mg/ml protein. To 0.5 ml portions of this homogenate were added 0.5 mlportions of an aqueous solution of salmon calcitonin (0.1 mg/ml). Theresults were incubated at 37° C., then the degradation fragments of thesalmon calcitonin in the reaction liquid were separated by HPLC (L-6200series (made by Hitachi, Ltd.) by 100% H₂ O from 0 to 5 minutes, 100% to50% H₂ O and 0 to 50% acetonitrile from 5 to 55 minutes). The amino acidsequences of the separated fragments were determined by an amino-acidsequencer (made by Applied Biosystems). The first fragment of salmoncalcitonin in human nasal mucosal homogenate are shown to Table 1.

                  TABLE 1                                                         ______________________________________                                        Degradation Fragments in Human Nasal                                          Mucosal Membrane Homogenate                                                   ______________________________________                                        Salmon calcitonin                                                                        Cys--Ser--Asn--Leu--Ser--Thr--Cys--                                fragment 1 Val--Leu--Gly--Lys                                                 (SEQ ID NO: 1)                                                                Salmon calcitonin                                                                        Leu--Ser--Gln--Glu--Leu--His--Lys--                                fragment 2 Leu--Gln--Thr--Tyr--Pro--Arg--Thr--                                (SEQ ID NO. 2)                                                                           Asn--Thr--Gly--Ser--Gly--Thr--Pro--NH.sub.2                        ______________________________________                                    

As shown in Table 1, the C end side of Lys of the peptide proteinaceousdrug is first cleaved in a human nasal mucosal homogenate. From this, itis guessed that the protease which first cleaves the peptideproteinaceous drug in the human nasal cavity is a trypsin-like enzyme.

A refined trypsin (made by Wako Pure Chemical Industry) was used,instead of the human nasal mucosal homogenate solution, in the sameprocedures followed as in (1) to separate the degradation fragments ofsalmon calcitonin in the reaction liquid by HPLC. In the same way as(1), the amino acid sequence was determined by an amino-acid sequencer.The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Salmon Calcitonin Degradation Fragments                                       by Trypsin                                                                    ______________________________________                                        Fragment 1      Cys--Ser--Asn--Leu--Ser--Thr--                                (SEQ ID NO: 2)  Cys--Val--Leu--Gly--Lys                                       Fragment 2      Leu--Ser--Gln--Glu--Leu--                                     (SEQ ID NO: 3   His--Lys                                                      Fragment 3 (SEQ ID NO: 4                                                                      Leu--Gln--Thr--Tyr--Pro--Arg                                  Fragment 4 (SEQ ID NO: 5                                                                      Thr--Asn--Thr--Gly--Ser--Gly--                                                Thr--Pro--NH.sub.2                                            ______________________________________                                    

As shown in Table 2, the degradation fragments of salmon calcitonincaused by refined trypsin are different from the degradation fragmentsof salmon calcitonin of Table 1. From this, it is guessed that thetrypsin-like enzyme present in the human nasal cavity is not trypsinitself.

Reference Experiment 2

A homogenate solution was prepared from human nasal mucosa to give 1mg/ml of protein. Next, synthesis substrates corresponding to thevarious proteases shown in Table 1 were added to 0.5 ml portions of thehomogenate solution to give 0.1 mM concentrations. The results wereincubated at 37° C. The amounts of the substrates remaining after apredetermined time were measured by HPLC to find the amounts ofsubstrates cleaved and find the activity of the various proteases. Theresults are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Activity of Protease in Human Nasal                                           Mucosal Homogenate                                                                                           Activity                                                          Corresponding                                                                             (nM/h/mg                                       Synthesized substrate                                                                            protease    protein)                                       ______________________________________                                        Boc--Gln--Ala--Arg--MCA                                                                          Trypsin     525                                            Boc--Val--Pro--Arg--MCA                                                                          α-Thrombin                                                                          269                                            Boc--Phe--Ser--Arg--MCA                                                                          Trypsin     250                                            Pro--Phe--Arg--MCA Kallikrein  85                                             Suc--Ala--Ala--Pro--Phe--MCA                                                                     Chymotrypsin                                                                              24                                             (SEQ ID NO: 6                                                                 Boc--Glu--Lys--Lys--MCA                                                                          Plasmin     14                                             Suc--Ala--Ala--Ala--MCA                                                                          Elastase    3                                              Bz--Arg--MCA       Trypsin     1                                              ______________________________________                                    

In the synthesis substrates, Boc means a t-Butyloxycarbonyl group, Sucmeans a Succinyl group, Bz means a Benzyl group, and MCA means4-Methyl-Coumaryl-7-Amide.

As shown in Table 3, a trypsin-like enzyme has a relatively highactivity in human nasal mucosal homogenate, while plasmin has aconsiderably low activity. However, there were some substratescorresponding to trypsin (in Table 3, Bz-Arg-MCA) which do not cleavemuch at all. Also, it became clear that the enzyme present in the humannasal mucosal homogenate is not trypsin itself. That is, it is guessedthat in the human nasal cavity, peptide proteinaceous drugs are mainlycleaved down by enzymes which are not trypsin, but have trypsin-likeactivity.

Reference Experiment 3

A homogenate solution was prepared from human nasal mucosa to give 1mg/ml of protein. Next, 0.25 ml portions of aqueous solutions (72 mM) ofthe different peptide proteinaceous drugs were added to 0.5 ml portionsof the homogenate solution, 0.01 ml portions of aqueous solutions (72M)of different enzyme inhibitors or absorption accelerants of the presentinvention were added, and the results were incubated at 37° C. Theamounts of the peptide proteinaceous drug not yet cleaved after apredetermined time were measured by HPLC to find the amounts ofdecomposition. The inhibition rates were calculated by the followingformula. The results are shown in Table 4.

Inhibition rate (%)=(A-B)/A×100

A: Amount of peptide proteinaceous drug cleaved when enzyme inhibitor orabsorption accelerant of present invention is not added to homogenate

B: Amount of peptide proteinaceous drug cleaved when enzyme inhibitor orabsorption accelerant of present invention is added to homogenate

ε-ACA: ε-Amino caproic acid

SCT: Salmon calcitonin

INS: Insulin

GIF: Somatostatin

ACTH: Adrenocorticotropic hormone

PTH: Parathyroid hormone

CGRP: Calcitonin gene related peptide

GLU: Glucogon

PDGF: Platelet-derived growth factor

S.p: Substance P

GHRH: Growth hormone releasing hormone

LHRH: Luteinizing hormone releasing hormone

                                      TABLE 4                                     __________________________________________________________________________    Inhibitory Effect on Degradation of Peptide Proteinaceous Drug in Human       Nasal Mucosal Homogenate By Various Protease Inhibitors                       Inhibitor (corresponding enzyme) or                                                             Inhibitor (%)                                               accelerant of present invention                                                                 SCT                                                                              INS                                                                              GIF                                                                              ACTH                                                                              PTH                                                                              CGRP                                                                              GLU PDGF                                                                              S.p                                                                              GHRH                                                                              LHRH                     __________________________________________________________________________    Aprotinin (trypsin)                                                                             14 18 22 11  15 20  25  7   25 15  15                       Gabexate (trypsin)                                                                              53 46 56 48  44 49  56  43  40 40  27                       Chymostatin (chymotrypsin)                                                                      38 22 25 12  15 23  35  10  15 25  16                       TPCK (chymotrypsin)                                                                             0  7  11 8   10 0   5   3   10 0   5                        Pepstatin (pepsin)                                                                              10 15 0  4   10 10  8   0   0  0   0                        ε-ACA (plasmin)                                                                         0  0  0  0   0  0   0   0   0  0   0                        Thiorphan (metalloprotease)                                                                     0  0  0  0   0  0   0   0   0  0   0                        Cyclohexane aminomethane                                                                        74 70 80 78  78 74  54  55  60 67  52                       Tranexamic acid   73 79 80 80  78 75  68  68  65 75  58                       Cetraxate hydrochloride                                                                         72 80 80 70  75 70  54  58  54 70  48                       Rotraxate hydrochloride                                                                         80 84 86 74  76 75  62  59  53 75  56                       Benzylamine       70 68 78 80  80 76  48  52  54 68  49                       p-Aminomethyl benzoic acid                                                                      76 74 85 84  80 72  60  65  58 70  54                       Mafenide acetate  67 52 74 78  75 70  56  59  55 66  32                       Dopamine hydrochloride                                                                          64 52 72 77  70 72  50  55  60 50  29                       __________________________________________________________________________

The Aprotinin, Gabexate, ACA, and Tranexamic acid used were made by WakoPure Chemical Industry, chymostatin was made by the Peptide Kenkyusho,TPCK and Thiorphan were made by Sigma Co., Pepstatin was made byBoehringer Mannheim Co., cetraxate hydrochloride was made by DaiichiPharmaceutical Co., the rotraxate hydrochloride was synthesized andrefined based on the description of Japanese Examined Patent Publication(Kokoku) No. 60-36418, the mafenide acetate was made by Tokyo Kasei Co.,and the dopamine hydrochloride was made by Wako Pure Chemical Industry.Furthermore the benzylamine was made by Wako Pure Chemical Industry andthe p-aminomethyl benzoic acid was made by Tokyo Kasei Co.

As shown in Table 4, it is clear that by including a trypsin inhibitor,the degradation of the peptide proteinaceous drug in the human nasalmucosal homogenate is obstructed. More surprisingly, it became clearthat tranexamic acid, which is not a trypsin inhibitor, and othercompounds of the present invention which are not trypsin inhibitors andare also not recognized as enzyme inhibitors, such as cyclohexanemethylamine, cetraxate hydrochloride, rotraxate hydrochloride,benzylamine, p-aminomethyl benzoic acid, mafenide acetate, dopaminehydrochloride, etc. have a function of inhibiting the degradation ofpeptide proteinaceous drugs higher than the trypsin inhibitors ofaprotinin and gabexate mesylate (Gabexate). This function is notobserved in 6-amino caproic acid (ε-ACA), so it is clear that it is notan inhibition function of plasmin. In other words, it is guessed thatthe enzymes which cleave peptide proteinaceous drugs in human nasalcavities are trypsin-like enzymes having the characteristic of beingremarkably restrained in activity by compounds of the present inventionlike tranexamic acid, cyclohexane methylamine, rotraxate hydrochloride,cetraxate hydrochloride, benzylamine, p-aminomethyl benzoic acid,mafenide acetate, and dopamine hydrochloride.

Example 1

Salmon calcitonin in an amount of 40 μg, tranexamic acid 40 μg,microcrystalline cellulose 30 mg, and magnesium stearate 15 μg weremixed in a mortar to prepare a tranexamic acid-added calcitonin nasalpowder. The powder was weighed to give 100 IU (20 μg) of calcitonin, waspacked in No. 2 capsules, then was administered to the right nasalcavities of three normal human volunteers by a Publizer (registeredtrademark, Teijin). After administration, 5 ml of blood was taken from avein in the forearm every certain period and the concentration of salmoncalcitonin in the plasma was measured by the RIA method. The results areshown in FIG. 1 by the time curve of the concentration of salmoncalcitonin in the plasma.

Control Example 1

The same procedure was followed as in Example 1, except that 40 μg oftranexamic acid was not added, to prepare a tranexamic acid-freecalcitonin nasal powder, the powder was weighed to give 100 IU (20 μg)of calcitonin and was packed in No. 2 capsules, then was administered tothree normal human volunteers in the same way as in Example 1, thenafter a certain time the concentration of salmon calcitonin in theplasma was measured. The results are shown together in FIG. 1.

Control Example 2

The same procedure was followed as in Example 1, except that use wasmade of 0.4 mg of aprotinin instead of the 40 μg of tranexamic acid inExample 1, to prepare an aprotinin-added calcitonin nasal powder, thepowder was administered to three normal human volunteers in the same wayas in Example 1, then after a certain time the concentration of salmoncalcitonin in the plasma was measured. The results are shown together inFIG. 1.

Example 2

Somatorein acetate (GHRH) in an amount of 2.0 mg, tranexamic acid 1.0mg, microcrystalline cellulose 30 mg, and magnesium stearate 15 μg weremixed in a mortar to prepare a tranexamic acid-added GHRH nasal powder.The powder was weighed to give a 1.0 mg amount of GHRH, was packed inNo. 2 capsules, and was administered to the right nasal cavities ofthree normal human volunteers in the same way as in Example 1, thenafter a certain time the concentration of growth hormone (GH) in theplasma was measured. The results are shown together in FIG. 2 by thetime curve of the concentration of GH in the plasma.

Control Example 3

The same procedure was followed as in Example 2, except that 1.0 mg oftranexamic acid was not added, to prepare a tranexamic acid-free GHRHnasal powder, the powder was weighed to give 1.0 mg of GHRH and waspacked in No. 2 capsules, then was administered to three normal humanvolunteers in the same way as in Example 2, then after a certain timethe concentration of GH in the plasma was measured. The results areshown together in FIG. 2.

Control Example 4

The same procedure was followed as in Example 2, except that use wasmade of 2.0 mg of gabexate mesylate instead of 1.0 mg of tranexamicacid, to prepare a gabexate mesylate-added GHRH nasal powder, the powderwas administered to three normal human volunteers in the same way as inExample 2, then after a certain time the concentration of GH in theplasma was measured. The results are shown together in FIG. 2.

Example 3

Deslorelin (LHRH derivative) in an amount of 0.2 mg, tranexamic acid 0.2mg, microcrystalline cellulose 30 mg, and magnesium stearate 15 μg weremixed in a mortar to prepare a tranexamic acid-added LHRH derivativenasal powder. The powder was weighed to give 1.0 mg of the LHRHderivative, was packed in No. 2 capsules, then was administered to theright nasal cavities of three normal human volunteers in the same way asin Example 1, then after a certain time the concentration ofleuteinizing hormone (LH) in the plasma was measured. The results areshown in FIG. 3 by the time curve of the LH concentration in the plasma.

Control Example 5

The same procedure was followed as in Example 3, except that 0.2 mg oftranexamic acid was not added, to prepare a tranexamic acid-free LHRHderivative nasal powder, the powder was weighed to give 1.0 mg of LHRHderivative and was packed in No. 2 capsules, then was administered tothree normal human volunteers in the same way as in Example 3, thenafter a certain time the concentration of GH in the plasma was measured.The results are shown together in FIG. 3.

Control Example 6

The same procedure was followed as in Example 3, except that use wasmade of 0.4 mg of aprotinin instead of 0.2 mg of tranexamic acid, toprepare an aprotinin-added LHRH derivative nasal powder, the powder wasadministered to three normal human volunteers in the same way as inExample 3, then after a certain time the concentration of LH in theplasma was measured. The results are shown in FIG. 3.

Example 4

Salmon calcitonin in an amount of 40 μg, rotraxate hydrochloride 40 μg,microcrystalline cellulose 30 mg, and magnesium stearate 15 μg weremixed in a mortar and mix to prepare a rotraxate hydrochloride-addedcalcitonin nasal powder. The powder was weighed to give 100 IU (20 μg)of calcitonin and was packed in No. 2 capsules, then was administered inthe right nasal cavity of three normal human volunteers by a Publizer(registered trademark, Teijin). After administration, 5 ml of blood wastaken from a vein in the forearm every certain period and theconcentration of salmon calcitonin in the plasma was measured by the RIAmethod. The results are shown in FIG. 4 by the time curve of theconcentration of salmon calcitonin in the plasma together with theresults of Comparative Examples 1 and 2.

Example 5

Salmon calcitonin in an amount of 40 μg, mafenide acetate 60 μg,microcrystalline cellulose 30 mg, and magnesium stearate 15 μg weremixed in a mortar to prepare a mafenide acetate-added calcitonin nasalpowder. The powder was weighed to give 100 IU (20 μg) of calcitonin andwas packed in No. 2 capsules, then was administered in the right nasalcavity of three normal human volunteers by a Publizer (registeredtrademark). After administration, 5 ml of blood was taken from a vein inthe forearm every certain period of 5 minutes, 15 minutes, 30 minutes,and 60 minutes, and the concentration of salmon calcitonin in the plasmawas measured by the RIA method. The results are shown in FIG. 5 by thetime curve of the concentration of salmon calcitonin in the plasma.

Example 6

The same procedure was followed as in Example 5, except that use wasmade of 50 μg of dopamine hydrochloride instead of 60 μg of mafenideacetate, to prepare a dopamine hydrochloride-added calcitonin nasalpowder. The powder was weighed to give 100 IU (20 μg) of calcitonin andwas packed in No. 2 capsules, then was administered to three normalhuman volunteers in the same way as in Example 5, then after a certaintime the concentration of salmon calcitonin in the plasma was measured.The results are shown together with the results of the above-mentionedComparative Examples 1 and 2 in FIG. 5.

INDUSTRIAL APPLICABILITY

According to the present invention, there is provided a peptideproteinaceous drug nasal powder composition which is improved inabsorbency and a peptide proteinaceous drug nasal powder compositionwhich is improved in absorbency and safe to the body.

    __________________________________________________________________________    SEQUENCE LISTING                                                              (1) GENERAL INFORMATION:                                                      (iii) NUMBER OF SEQUENCES: 6                                                  (2) INFORMATION FOR SEQ ID NO: 1:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1:                                      CysSerAsnLeuSerThrCysValLeuGlyLys                                             1510                                                                          (2) INFORMATION FOR SEQ ID NO: 2:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2:                                      LeuSerGlnGluLeuHisLysLeuGlnThrTyrProArgThrAsn                                 151015                                                                        ThrGlySerGlyThrPro                                                            20                                                                            (2) INFORMATION FOR SEQ ID NO: 3:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3:                                      LeuSerGlnGluLeuHisLys                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO: 4:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4:                                      LeuGlnThrTyrProArg                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO: 5:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5:                                      ThrAsnThrGlySerGlyThrPro                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO: 6:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6:                                      AlaAlaProPhe                                                                  __________________________________________________________________________

We claim:
 1. A peptide proteinaceous drug nasal powder compositioncomprising (i) an absorption accelerant comprising a compound, or itssalt, having in the compound molecule a group expressed by the formula(II): ##STR10## wherein, represents a cyclohexane ring or a benzenering; n is an integer of 1 or 2; R¹, R² and R³ are, independently, amember selected from the group consisting of a hydrogen atom -COOR,-COR, -OR', and -SO₂ NH₂, which may be substituted; provided that atleast one of R¹, R² or R³ is a hydrogen atom; R represents a hydrogenatom, a C₁ -C₆ lower alkyl group which may be substituted, or CH₂ CH₂COOR'; R' represents a hydrogen atom, a C₁ -C₆ lower alkyl group whichmay be substituted, a phenyl group which may be substituted, or a C₇ -C₈aralkyl group which may be substituted, and (ii) a therapeuticallyeffective amount of a peptide proteinaceous drug.
 2. A nasal powdercomposition as set forth in claim 1, wherein ##STR11## in formula (II)is a cyclohexane ring and n=1.
 3. A nasal powder composition as setforth in claim 2, wherein the cyclohexane ring is substituted by amember selected from the group consisting of a hydrogen atom, -CO-C₆ H₅-(CH₂)₂ COOH, a carboxyl group, and -COO-C₆ H₅ -(CH₂)₂ COOH.
 4. A nasalpowder composition as set forth in claim 2, wherein R¹ and R³ in formula(II) are each a hydrogen atom and R² is -COO -CH₆ H₅ -(CH₂)₂ COOH.
 5. Anasal powder composition as set forth in claim 2, wherein R¹ and R³ informula (II) are each a hydrogen atom and R² is -CO-C₆ H₅ -(CH₂)₂ -COOH.6. A nasal powder composition as set forth in claim 2, wherein R¹ and R³in formula (II) are each a hydrogen atom and R² is a carboxyl group. 7.A nasal powder composition as set forth in claim 1 wherein ##STR12## informula (II) is a benzene ring.
 8. A nasal powder composition as setforth in claim 7, wherein the benzene ring is substituted by a memberselected from the group consisting of a hydrogen atom, a carboxyl group,a hydroxyl group and a sulfamine group.
 9. A nasal powder composition asset forth in claim 7, wherein R¹ and R³ in formula (II) are each ahydrogen atom, R² is a carboxyl group and n is
 1. 10. A nasal powdercomposition as set forth in claim 7, wherein R¹ and R³ in formula (II)are each a hydrogen atom, R² is a sulfamine group, and n is
 1. 11. Anasal powder composition as set forth in claim 7, wherein, in formula(II), R¹ is a hydrogen atom, R² and R³ are each a hydroxyl group, and nis
 2. 12. A nasal powder composition as set forth in claim 1, whereinthe peptide proteinaceous drug is at least one peptide proteinaceousdrug selected from the group consisting of calcitonins, insulins,somatostatin (GIF)and derivatives thereof, parathyroid hormones (PTH),substance P, platelet derived growth factors (PDGF), galanin, gastrin,neurokinins, interleukins, neurotensin, endo serine, growth hormones(GH), growth hormone-releasing hormone (GHRH) and derivatives thereof,growth hormone releasing factor (GRF), luteinizing hormone-releasinghormone (LHRH) and derivative thereof, enkephalin and derivativesthereof, secretin, bradykinin and derivatives thereof,adrenocorticotrophic hormone (ACTH) and derivatives thereof, glucagon,insulin growth factor (IGF), calcitonin gene related peptide (CCRP)interferons, vasopressin and derivatives thereof, atrial natrium peptide(ANP), erythropoietin, and granulocyte colony stimuli factor (G-CSF).13. A nasal powder composition as set forth in claim 1, wherein thepeptide proteinaceous drug is at least one peptide proteinaceous drugselected from the group consisting of calcitonins, insulins,somatostatin (GIF) and derivatives thereof, parathyroid hormones (PTH),substance P, platelet derived growth factors (PDGF), growthhormone-releasing hormone (GHRH) and derivatives thereof, luteinizinghormone-releasing hormone (LHRH) and derivatives thereof,adrenocorticotrophic hormone (ACTH) and derivatives thereof, glucagon,and calcitonin gene related peptide (CGRP).
 14. A nasal powdercomposition as set forth in claim 1, wherein the peptide proteinaceousdrug is at least one peptide proteinaceous drug selected from the groupcomprising salmon, eel, human, pig, and chicken natural calcitonin andderivatives thereof.
 15. A nasal powder composition as set forth inclaim 1, wherein the peptide proteinaceous drug is at least one peptideproteinaceous drug selected from the group consisting of human, rat, andpig natural somatostatin and derivatives thereof.
 16. A nasal powdercomposition as set forth in claim 1, wherein the peptide proteinaceousdrug is at least one peptide proteinaceous drug selected from the groupconsisting of bovine, human, and rat natural parathyroid hormone (PTH)and derivatives thereof.
 17. A nasal powder composition as set forth inclaim 1, wherein the peptide proteinaceous drug is at least one peptideproteinaceous drug selected from the group consisting of bovine, human,rat, and pig natural luteinizing hormone-releasing hormone (LHRH) andderivatives thereof.
 18. A nasal powder composition as set forth inclaim 1, wherein the peptide proteinaceous drug is at least one peptideproteinaceous drug selected from the group consisting of human, rat, andpig natural growth hormone-releasing hormone (GHRH) and derivativesthereof.